1. Identification of a new form of autophagy for synaptic vesicles. Synaptic vesicles are small spherical organelles in the presynaptic terminals of neurons. They contain neurotransmitter and release neurotransmitter when the presynaptic membrane is depolarized by action potentials. After exocytosis, vesicles are retrieved by endocytosis and recycled to form new synaptic vesicles. The number of synaptic vesicles at a synapse is an important factor determining synaptic strength, which is dynamically regulated during development and by experience. A stable, yet flexible, pool of synaptic vesicles is therefore critical to ensure the reliability and adaptability of neural circuits. Much has been known about the machinery and regulation of vesicle exocytosis and endocytosis. The route of vesicle trafficking post endocytosis, by contrast, is less clear. Multiple lines of evidence indicate that at least a fraction of endocytic synaptic vesicles go through the endosomal system. The activity of synaptic endosomes is necessary for endocytosis and exocytosis of synaptic vesicles. However, little is known about the role of synaptic endosomes in the synaptic vesicle cycle. Although synaptic vesicles have been intensively studied, how their number is maintained and regulated remains largely unclear. Endosomes can fuse with autophagosomes to form amphisomes. Autophagosomes are doublemembrane structures formed during autophagy, a process by which organelles and aggregated proteins are delivered to lysosomes for degradation. Autophagy serves as a pro-survival mechanism during stress induced by, for instance, starvation or growth factor withdrawal. Various organelles can be cargos of autophagy. Selective autophagy for organelles (such as mitophagy for mitochondria, ribophagy for ribosomes, pexophagy for peroxisomes, and reticulophagy for endoplasmic reticulum) has been uncovered. In neurons, however, the physiological significance of autophagy for synaptic vesicles remains elusive. In this project, we found that the activity of autophagy is essential for the homeostasis and activity-dependent cycling of synaptic vesicles in hippocampal neurons. Synaptic vesicles are recruited to autophagosomes via early and late endosomes, and autophagy of synaptic vesicles is regulated by synaptic excitation. Our study therefore elucidates a new type of autophagy for synaptic vesicles and reveals a new mechanism underlying the cycling of synaptic vesicles. 2. The mechanism by which the schizophrenia risk gene dysbindin contributes to synaptopathology in schizophrenia. Dysbindin is a coiled-coil domain containing protein, initially discovered as a dystrophin-binding protein and later found to be one of eight subunits of biogenesis of lysosome-related organelles complex 1 (BLOC-1). Single-nucleotide polymorphisms of the dysbindin gene (Dtnbp1) have been associated with higher risk for schizophrenia, and the postmortem brains of schizophrenia patients consistently exhibit low levels of dysbindin proteins and mRNAs. Our earlier work shows that dysbindin contributes to the establishment of neuronal connectivity by regulating the development of dendritic protrusions, including dendritic spines (tiny dendritic protrusions where excitatory synapses are formed) and filopodia (long, thin protrusions that predominant in young neurons). Dysbindin, therefore, may confer the risk for schizophrenia by regulating the development of dendritic spines. To determine how dysbindins regulates spine development in this reporting period, we investigated the associated proteome of dysbindin in the P2 synaptosome fraction of mouse brain. Our data suggest that dysbindin has three isoforms associating with different complexes in the P2 fraction of mouse brain. To facilitate immunopurification, we generated BAC transgenic mice expressing a tagged dysbindin and using the transgenic mice identified 47 putative dysbindin-associated proteins, including all components of BLOC-1, by mass spectrometry. We confirmed the interaction of dysbindin with several identified proteins, including WDR11, FAM91A1, snapin, muted, pallidin, and two proteasome subunits, PSMD9 and PSMA4 by co-immunoprecipitation. We also found that proteasomal activity is significantly reduced in the P2 fraction from the brains of dysbindin-null mutant (sandy) mice. Our data suggest that dysbindin is functionally interrelated to the ubiquitin-proteasome system and offer a molecular repertoire for future study of dysbindin functional networks in brain.